Fatty acid amide hydrolase (FAAH), referred to as oleamide hydrolase and anandamide amidohydrolase in early studies, is an integral membrane protein that degrades fatty acid primary amides and ethanolamides including oleamide and anandamide, as illustrated in FIG. 1 (M. P. Patricelli, et al., (1998) Biochemistry 37, 15177-15187. D. G. Deutsch, et al., (1993) Biochem. Pharmacol. 46, 791-796; F. Desarnaud, et al., (1995) J. Biol. Chem. 270, 6030-6035; C. J. Hillard, et al., (1995) Biochim. Biophys. Acta 1257, 249-256; N. Ueda, et al., (1995) J. Biol. Chem. 270, 23823-23827; R. L. Omeir, et al., (1995) Life Sci. 56, 1999-2005; S. Maurelli, et al., (1995) FEBS Lett. 377, 82-86; and M. Maccarrone, et al., (1998). J. Biol. Chem. 273, 32332-32339). The distribution of FAAH in the CNS suggests that it degrades neuromodulating fatty acid amides at their sites of action and is intimately involved in their regulation (E. A. Thomas, et al., (1997) J. Neurosci. Res. 50, 1047-1052). FAAH hydrolyzes a wide range of oleyl and arachidonyl amides, the CB1 agonist 2-arachidonylglycerol, the related 1-arachidonylglycerol and 1-oleylglycerol, and methyl arachidonate, illustrating a range of bioactive fatty acid amide or ester substrates. (W. Lang, et al., (1999) J. Med. Chem. 42, 896-902; S. K. Goparaju, et al., (1998) FEBS Lett. 442, 69-73; Y. Kurahashi, et al., (1997) Biochem. Biophys. Res. Commun. 237, 512-515; and T. Bisogno, et al., (1997) Biochem. J. 322, 671. Di Marzo, V., T. Bisogno, et al., (1998) Biochem. J. 331, 15-19). Although a range of fatty acid primary amides are hydrolyzed by the enzyme, FAAH appears to work most effectively on arachidonyl and oleyl substrates (B. F. Cravatt, et al., (1996) Nature 384, 83-87; and D. K. Giang, et al., (1997) Proc. Natl. Acad. Sci. USA 94, 2238-2242).
The important biological role of FAAH suggests a need for molecular regulators of its activity. However, only a select set of FAAH inhibitors have been disclosed. Amongst these is the potent endogenous inhibitor 2-octyl γ-bromoacetoacetate, which was discovered prior to FAAH and characterized as an endogenous sleep-inducing compound (M. P. Patricelli, et al., (1998) Bioorg. Med. Chem. Lett. 8, 613-618; and S. Torii, et al., (1973) Psychopharmacologia 29, 65-75). After the discovery of FAAH, elaborations of 2-octyl γ-bromoacetoacetate were developed and characterized as potent inhibitors of this enzyme. Moreover, subsequent inhibitors employ a fatty acid stricture attached to pharmacophoric head group. The pharmacophoric head groups can generally be classified as either reversible or irreversible. Reversible inhibitors include electrophilic carbonyl moieties, e.g., trifluoromethyl ketones, α-halo ketones, α-keto esters and amides, and aldehydes. Irreversible inhibitors include sulfonyl fluorides and fluorophosphonates. (B. Koutek, et al., (1994) J. Biol. Chem. 269, 22937-22940; J. E. Patterson, et al., (1996) J. Am. Chem. Soc. 118, 5938-5945; D. L. Boger, et al., (1999) Bioorg. Med. Chem. Lett. 9, 167-172; D. G. Deutsch, et al., (1997) Biochem. Pharmacol. 53, 255-260. D. G. Deutsch, et al., (1997) Biochem. Biophys. Res. Commun. 231, 217-221; and L. De Petrocellis, et al., (1997) Biochem. Biophys. Res. Commun. 231, 82-88; and L. De Petrocellis, et al., (1998) In Recent Advances Prostaglandin, Thromboxane, and Leukotriene Research, Plenum Press: New York, 259-263).